We are investigating the role of prostaglandin H synthases (PGHS) in allergen-induced pulmonary inflammation and airway hyperresponsiveness using PGHS-1-/- and PGHS-2-/- mice. Bronchoalveolar lavage fluid (BAL) PGE2 is lower in nonimmunized PGHS-1-/- mice compared to wild type or PGHS-2-/- mice, but there are no significant differences in basal lung function or histopathology. Following allergen challenge, lung inflammatory indices (BAL cells, proteins, IgE and lung histopathology) are significantly greater in PGHS-1-/- compared with PGHS-2-/- mice, and both are far greater than in wild type mice. Both allergic PGHS-1-/- and PGHS-2-/- mice exhibit decreased baseline lung compliance compared with allergic wild type mice, while only allergic PGHS-1-/- mice show increased baseline lung resistance and responsiveness to methacholine. Allergen exposure causes a modest increase in lung PGHS-2 protein and a corresponding increase in BAL PGE2 in wild type mice. Thus, PGHS-1 is the predominant enzyme that biosynthesizes PGE2 in normal mouse lung, both PGHS-1 and PGHS-2 products limit allergic lung inflammation and promote lung function, and there is a dissociation between the presence of airway inflammation and the development of airway hyperresponsiveness in PGHS-2 deficient mice. More recently, we have examined the effects of disruption of Pghs genes on pulmonary responses to endotoxin (bacterial lipopolysaccharide, LPS) exposure. All mice exhibit increased lung resistance and methacholine responsiveness following LPS exposure; however, these changes are much more pronounced in PGHS-1-/- relative to PGHS-2-/- and wild type mice. Interestingly, there are no significant differences in BAL cells or lung histopathology between the genotypes despite reduced BAL cytokines and PGE2 in both the PGHS-1-/-and PGHS-2-/- mice relative to wild type mice. Based on these data, we concluded that airway inflammation and hyperresponsiveness are dissociated in PGHS-1-/- mice exposed to LPS, and that the balance of PGHS-1 and PGHS-2 is important in regulating physiologic but not inflammatory responses to inhaled LPS. Future studies will: (a) elucidate the mechanisms whereby PGHS-derived eicosanoids modulate the lung immune response to inhaled allergens; (b) investigate the PGHS-dependent mechanisms involved in the inflammatory response to endotoxin inhalation; and (c) utilize well characterized pulmonary infectivity models to evaluate host resistance to intracellular and extracellular pathogens and to determine if there is an innate defect in T cell function in the PGHS deficient mice.